The long term concern of this laboratory has been the study of the heme biosynthetic pathway under both physiologic and pathologic situations. It will be our primary goal to investigate the mechanisms which normally operate to control this important biochemical sequence and to learn how they are related not only to normal cellular synthesis of porphyrins, heme and hemoglobin, but to cell differentiation, hepatic and erythroid drug toxicity, refractory anemias and the porphyrias. More specificially, we plan to investigate the role of the "regulatory" pool of heme on the controlling heme enzymes and how this in turn effects total cell function, maturation, and differentiation. In particular, we will be investigating the effect of various agents such as heavy metals, benzene, interferon and certain steroids on the degradation of heme particularly as they relate to induction of heme oxygenase activity. In addition, we will try to relate perturbations of the biochemical events culminating in heme formation to the cell-cell interactions which have been noted to occur in in vitro development of erythroid colonies. These colonies will also serve as a model system for investigating the sequential appearance of the heme enzymes as they are related to erythroid maturation and differentiation. They will also prove to be a useful tool in the study of the effects of certain chemicals, hormones and xenobiotics on erythroid differentiation.